Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-06-11
2004-05-04
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06730692
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to methods for treating and/or preventing tissue and cell damage caused by reactive oxygen species in mammals. More specifically, the present invention relates to the prevention and/or reduction of tissue and cell damage through the administration of histamine and histamine agonists.
The complete reduction of one molecule of O
2
to water is a four-electron process. Oxidative metabolism continually generates partially reduced species of oxygen, which are far more reactive, and hence more toxic than O
2
itself. A one-electron reduction of O
2
yields superoxide ion (O
2
−
); reduction by an additional electron yields hydrogen peroxide (H
2
O
2
), and reduction by a third electron yields a hydroxyl radical (OH.), and a hydroxide ion. Nitrous oxide (NO), is another interesting reactive oxygen metabolite, produced through an alternative pathway. Hydroxyl radicals in particular are extremely reactive and represent the most active mutagen derived from ionizing radiation. All of these species are generated and must be converted to less reactive species if the organism is to survive.
Particular cells of the immune system have harnessed the toxic effects of ROMs as an effector mechanism. Professional phagocytes, polymorphonuclear leukocytes (neutrophils, PMN), monocytes, macrophages, and eosinophils function to protect the host in which they reside from infection by seeking out and destroying invading microbes. These phagocytic cells possess a membrane-bound enzyme system which can be activated to produce toxic oxygen radicals in response to a wide variety of stimuli.
The “increased respiration of phagocytosis” (the respiratory burst) was reported and thought to be a result of increased mitochondrial activity providing additional energy for the processes of phagocytosis. It was later shown that a non-mitochondrial enzymatic system produced the increased levels of oxygen metabolites since the respiratory burst continued even in the presence of mitochondrial inhibitors such as cyanide and antimycin A. In 1968, Paul and Sbarra showed clearly that hydrogen peroxide was produced by stimulated phagocytes and in 1973 Babior and co-workers established that superoxide was a major product of the oxidase. (Paul and Sbarra,
Biochim Biophys Acta
156(1):168-78 (1968); Babior, et al.,
J Clin Invest
52(3):741-4 (1973). It is now generally accepted that the enzyme is membrane bound, exhibits a preference for NADPH (K
m
=45 &mgr;M) over NADH (K
m
=450 &mgr;M), and converts oxygen to its one electron-reduced product, superoxide.
NADPH+H
+
+2O
2
→NADP
+
+2H
+
+2O
2
−
The hydrogen peroxide arises from subsequent dismutation of the superoxide.
2O
2
−
+2H
+
→H
2
O
2
+O
2
−
The enzyme activity is almost undetectable in resting (unstimulated) phagocytes, but increases dramatically upon stimulation. In patients with the rare genetic disorder chronic granulomatous disease (CGD), there is a severe predisposition to chronic recurrent infection. The neutrophils from these patients phagocytose normally but the respiratory burst is absent and NADPH oxidase activity (and radical production) is undetectable, indicating that the oxidase and its product, the reactive oxygen metabolites, have an important bactericidal function.
Neutrophils and macrophages produce oxidizing agents to break through the protective coats or other factors that protect phagocytosed bacteria. The large quantities of superoxide, hydrogen peroxide, and hydroxyl ions are all lethal to most bacteria, even when found in very small quantities.
While there are beneficial effects of these oxygen metabolites, it is clear that inappropriate production of oxygen metabolites can result in severely deleterious effects. Several disease states illustrate this point, including various inflammatory diseases, including rheumatoid arthritis, Crohn's disease, and Adult Respiratory Distress Syndrome (ARDS). An effective method to reduce and/or minimize the production and release of ROMs in patients suffering from a variety of disparate diseases would be a great boon to medicine and service to reduce and eliminate a substantial amount of human suffering.
SUMMARY OF THE INVENTION
The present invention provides a novel method for inhibiting and reducing enzymatically produced ROM-mediated oxidative damage. In accordance with one aspect of the present invention, there is provided a method for inhibiting and reducing enzymatically produced ROM-mediated oxidative damage in a subject comprising the step of administering a compound effective to inhibit the production or release of enzymatically produced reactive oxygen metabolites to a subject suffering from a condition caused or exacerbated by enzymatically produced ROM-mediated oxidative damage.
In one embodiment, the reactive oxygen metabolites are released constitutively. Alternatively, the reactive oxygen metabolites are released in response to a respiratory burst. In another embodiment of the present invention, the condition is selected from the group consisting of ARDS, ischemia or reperfusion injury, infectious disease, autoimmune or inflammatory diseases, and neurodegenerative diseases.
In another embodiment of the present invention, the compound is selected from the group consisting of histamine, H
2
receptor agonists, NADPH oxidase inhibitors, serotonin and serotonin agonists. One embodiment further comprising the step of administering an effective amount of a ROM scavenger. In the embodiment where a ROM scavenger is administered, the step of administering the ROM scavenger results in ROM scavenger catalyzed decomposition of ROMs. In still another embodiment, the scavenger is selected from the group consisting of catalase, glutathione peroxidase, ascorbate peroxidase, superoxide dismutase, glutathione peroxidase, ascorbate peroxidase, vitamin A, vitamin E, and vitamin C.
In accordance with still another aspect of the present invention, there is provided a method for treating a subject suffering from a disease state wherein phagocyte produced ROM-mediated oxidative damage can occur, comprising the steps of identifying a subject with a condition in which enzymatically generated ROMs released in response to a respiratory burst produce ROM-meditated oxidative damage and administering a compound effective to inhibit the production or release of ROMs.
In one embodiment, the condition is selected from the group consisting of ARDS, ischemia or reperfusion injury, infectious disease, autoimmune or inflammatory diseases, and neurodegenerative diseases. In another embodiment, the step of administering the compound further comprises administering a compound selected from the group comprising histamine, H
2
receptor agonists, serotonin, serotonin agonists, and NADPH oxidase inhibitors. Another embodiment, further comprising administering an effective amount of a ROM scavenger. In the embodiment where a ROM scavenger is administered, the step of administering the ROM scavenger results in the reactive oxygen metabolites scavenger catalyzed decomposition of reactive oxygen metabolites. In still another embodiment, the step of administering the reactive oxygen metabolites scavenger further comprises administering a compound selected from the group consisting of catalase, superoxide dismutase, glutathione peroxidase, and ascorbate peroxidase.
In accordance with still another aspect of the present invention, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier, a compound effective to inhibit the production or release of enzymatically generated ROMs and a compound effective to scavenge ROMs. In one embodiment, the compound effective to inhibit the production or release of ROMs is selected from the group consisting of histamine, H
2
receptor agonists, serotonin, serotonin agonists, and NADPH oxidase inhibitors. In another embodiment, the compound effective to scavenge ROMs is selected from the group consisting of catalase,
Gehlsen Kurt R.
Hellstrand Kristoffer
Hermodsson Svante
Knobbe Martens Olson & Bear LLP
Maxim Pharmaceuticals, Inc.
Spivack Phyllis G.
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